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WO2003037343A1 - Composition a base d'acide folique et de carnitine, favorisant la fertilite masculine - Google Patents

Composition a base d'acide folique et de carnitine, favorisant la fertilite masculine Download PDF

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Publication number
WO2003037343A1
WO2003037343A1 PCT/EP2002/011201 EP0211201W WO03037343A1 WO 2003037343 A1 WO2003037343 A1 WO 2003037343A1 EP 0211201 W EP0211201 W EP 0211201W WO 03037343 A1 WO03037343 A1 WO 03037343A1
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WO
WIPO (PCT)
Prior art keywords
carnitine
folic acid
composition
male
present
Prior art date
Application number
PCT/EP2002/011201
Other languages
English (en)
Inventor
Paula Gaynor
Original Assignee
Lonza Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lonza Ag filed Critical Lonza Ag
Publication of WO2003037343A1 publication Critical patent/WO2003037343A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings

Definitions

  • the present invention relates to compositions comprising folic acid and carnitine and to uses thereof.
  • EP-B1-1039 894 devises a mixture of L-carnitine and Acetyl-L-carnitine for increasing male sperm quality.
  • the amount of that composition intended for human administration is in the range of several grams of substance; apart from cost considerations for human consumers, such amounts may cause symptoms of diarrohea if taken in amounts of >3 g a day.
  • compositions according to claim 1 and a use therof according to claim XXX comprise Carnitine or an Acyl-Carnitine or a salt thereof and folic acid or a salt thereof.
  • Folic acid, or folate is known to be a carrier of CI -units in the organism. Folic acid is also known under the non-systematic name of pteroylglutamic acid (PGA). Under folic acid in the context of the present invention, any known active metabolic equivalent of folic acid is to be understood, e.g. folate, tetrahydrofolate, 5- methyl-tetrahydrofolate, 5,10-methylentetrahydrofolate, 10-formyltetrahydrofolate.
  • the folic acid is 5-methyl-tetrahydrofolate, 5,10-methylentetrahydrofolate or salts thereof. Most preferably, the folic acid is 5-methyl-tetrahydrofolate.
  • the methylated form of folic acid (including its salts which dissolve in the gastrointestinal tract) is the form actually absorbed most optimally in the intestine amongst all CI -modified forms of folic acid; non-methylated folic acid is converted to the methyl form for transport across the intestinal barrier by specialized enzyme systems.
  • such folic acid is man-made and is not comprised as a natural compound of food stuff. Due to this, the folic acid content of the present composition is most efficiently absorbed in the guts. - Foods deliver folate mostly in the 'bound' form, that is, combined with a string of amino acids, predominantly glutamate, therefore termed 'polyglutamate'. The intestine prefers to absorb the free folate form, prejudice to the above said on specific methylation systems for efficient transport. Due to this, nutritionists calculate the folic acid contents of diets in dietary folate equivalents (DFE): Synthetic folate is considered to be 1.7 more potent (1.7 DFE) upon ingestion than naturally comprised dietary 'folate'.
  • DFE dietary folate equivalents
  • Carnitine according to the present invention may be (DL)-Carnitine or, preferably, essentially pure L-Carnitine.
  • Such Carnitine may as well be Acyl-Carnitine, in particular 2- Acetyl-Carnitine.
  • Such Carnitine may be employed either as an inner salt or as a simple or complex salt together with other ionic substances such as, but not limited to, chloride, fumarate, tartrate, citrate, isocitrate, (-)-hydroxycitrate, magnesium, calcium, cholin, either alone or in suitable combinations, particularly as non-hygroscopic complex salts, e.g.
  • Carnitine is either L-Carnitine-tartrate, L-Carnitine-magnesium-citrate or L-Carnitine- magnesium-(-)-hydroxycitrate.
  • Carnitine is, in its L-form, a naturally occurring substance involved in energy metabolism in mitochondria that is widely used as a nutritional supplement, e.g. for slimming and is a well-known substance without adverse effects.
  • the composition of the present invention displays a synergistic, male fertility enhancing effect.
  • Sperm count and density of sperm cells with normal, non-pathologic morphology are synergistically enhanced.
  • L- carnitine contributes to sperm motility.
  • Sperm count and density can be determined using standard microscopic techniques (Adelmann, M. eta 1., Atlas of sperm cell morphology, Chicago, ASCP Press, 1989; Schover, L. et al., Overcoming Male Infertility, New York, Wiley, 2000).
  • sperm count is determined according to the method of Overstreet, J. et al.
  • sperm concentration relates to the number of sperm that is found in each milliliter of semen
  • the sperm count - total sperm count - is the total number of sperm opresent in the semen (semen volme multiplied by sperm concentration). This value accurately describes the sperm production by the testicles. Briefly, appropriate dilutions of semen (1:10 or 1:20 using w3ater were applied to a Neubauer hemacytometer (Fisher, Pittsburgh, PA), allowed to settle and counted. From this count, density (10 6 sperm/mL) was determined, and total count was calculated by multiplying the density by the measured ejaculate volume.
  • the normal value for sperm concentration is approx. > 20 million/ml.
  • the normal total sperm count is > 40 million.
  • the composition and its use, respectively, according to the present invention is most effective in individuals having abnormally lowered values of sperm count and density as compared to these standard values.
  • the male person to whom the composition according to the present invention is administered has a daily intake of folic acid, calculated as DFE, that is below the recommended 400 ⁇ g/day of folic acid according the RDA guidelines (RDA: Recommended daily allowance; US health services).
  • the blood plasma total folate concentration should thus be below a threshold of about 7nmol/L as is easily determined by commercial radio immunoassy (Quantaphase B-12 folate Radioassay; BioRad, Hercules, CA). It should be noted that folate is comprised mostly in fresh vegetables or certain fruits, but is very poorly present e.g. in milk products.
  • storage/processing of foods, and in particular cooking of food very efficiently destroys folic acid in foodstuffs. Only raw, fresh vegetables or freshly prepared orange juice do provide sufficient amounts of folic acid if taken in effective amounts.
  • the male person to to whom the composition according to the present invention is administered is deficient in folic acid for other reasons than insufficient nutritional intake.
  • Deficiency in this context does not relate to lowered total levels of folate e.g. in blood plasma.
  • the blood plasma levels in such individuals are not significantly lowered as compared to healthy, balancedly fed individuals. Rather, the metabolic balance of biochemically active methyl- and non-methyl derivatives of tetrahydrofolic acid is shifted.
  • the deficiency consists in lowered amount of non-methyl tetrahydrofolic acid. For instance, it has been observed that medicaments, e.g.
  • a male-fertility affecting deficiency in non-methyl tetrahydrofolic acid or its corresponding salt is determined by measuring the concentration of folates in seminal plasma (according to the method of Tamura, T.,
  • the person administered the present composition does not need to be abnormally deficient in carnitine.
  • L-carnitine can be taken over a wide range of dosage with ever improving effect up to the range of several grams.
  • a further beneficial side effect of carnitine administration is the reduction of serum cholesterol levels based on metabolic effects (Cacciatore, L. et al., (1991), Drugs Exp. Clin. Res. 18, 355 ff.). This further promotes a patient's health.
  • Folic acid itself is an essential vitamin needed for anabolic acitivities (nucleotide synthesis, aminoacid synthesis) in the body.
  • the composition in accordance with the present invention comprises at least 5 mg up to 8000 mg carnitine per 100 ⁇ g of folic acid inhibitor, more preferably 100 to 2000 mg carnitine per 100 ⁇ g of folic acid, most preferably 250 to 850 mg carnitine per 100 ⁇ g of folic acid.
  • the folic acid may amount to between 10 to 1000 ⁇ g, preferably between 40 to 400 ⁇ g in suitable oral dosage forms comprising the composition of the present invention.
  • a daily dose for folic acid supplementing the diet can be 50-300 ⁇ g for an average adult and is achieved by multiple oral intake of a capsule or tablet.
  • Carnitine may amount to between 50 to 8000 mg in suitable oral dosage forms of the composition. Preferably, it amounts to in between 250 to 1000 mg for the purpose of enhancing the male fertility.
  • the composition of the present invention should be administered for at least 2-4 weeks prior to detecting the effect on sperm quality as described above.
  • the present invention should essentially work in mammalian males of all species, preferably it works in humans. More preferably, said human males are older than 30 years of age. At this age, folic acid metabolism is more easily disturbed and a deficiency in non-methyl tetrafolic acid provoked than in younger human males.
  • composition according to the present invention may be added to foodstuff, i.e. the diet, or swallowed as a freshly prepared suspension.
  • the composition may be added to low-calorific cereal or chocolate bars or similiar snacks comprising a certain amount of fat.
  • Dispersible powders and granules comprising the composition according to the present invention are a prefered embodiment.
  • Such powders or granules may be suitable for preparation of an aqueous suspension by the addition of water and may provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • the composition is prepared as an oral dosage form and may comprises further, pharmaceutically acceptable exciepients.
  • excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch and alginic acid; binding agents such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated with known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl stearate alone or with a wax may be employed.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as corn starch and alginic acid
  • binding agents such as starch, gelatin or acacia
  • oral dosage forms such as tablets, capsules or microbeads are coated with an enteric coating which prevents dissolution in the acidic environment of the stomach. Instead, this coating dissolves in the small intestine at a more neutral pH.
  • Complex organic molecules such as lipase inhibitors, in particular lipstatin, are susceptible in varying degrees to acid hydrolysis.
  • enteric coated compositions are described by Bauer et al. (Coated Pharmaceutical Dosage Forms: Fundamentals, Manufacturing Techniques, Biopharmaceutical Aspects, Test Methods and Raw Materials, CRC Press, Washington, D.C., 1998) .
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Oil suspensions may be formulated by suspending the active ingredients in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agent such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by an added antioxidant such as ascorbic acid.
  • Additional excipients for example sweetening, flavoring and coloring agents, may also be present. It is also possible to add further slimming agents such as glycosidase inhibitors, e.g. acarbose, whose funciton is to hinder breakdown of carbohydrates such as starch in the intestine. This further reduces the calorific value of the diet.
  • further slimming agents such as glycosidase inhibitors, e.g. acarbose, whose funciton is to hinder breakdown of carbohydrates such as starch in the intestine. This further reduces the calorific value of the diet.
  • the composition of the present invention further comprises one or several vitamins such as e.gNitamine A, Vitamine D or Nitamine E.
  • Such composition may further comprise essential fatty acids such as linolic acid, linolenic acid or omega-3 polyunsatured fatty acids.
  • Such pharmaceutical dosage forms might be e.g. gelatine capsules having a partitioning wall or double walled capsules consisting essentially of two separate capsules one being inserted into the other.
  • kits-of-parts are a grouping of separate blister bags comprised in a single package.
  • Composition and pharmaceutical dosage form comprising Carnitine (commercial L- Carnitine, Lonza Ltd.) and folic acid.
  • a hard gelatine capsule is filled with approx. 447 mg of a powder mixture.
  • the particle size is ⁇ 0.8 ⁇ m.
  • the powder has been mixed by addition of the fine-milled, solid compounds in a conventional knedding machine.
  • the composition of the powder mixture is given below:
  • L-Carnitine (Carnitine-Mg-Citrate, Lonza Ltd.) 300 mg folic acid 400 ⁇ g of folic acid

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition et son utilisation de façon à favoriser la fertilité masculine.
PCT/EP2002/011201 2001-10-30 2002-10-07 Composition a base d'acide folique et de carnitine, favorisant la fertilite masculine WO2003037343A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP01125858 2001-10-30
EP01125858.9 2001-10-30
US33314501P 2001-11-27 2001-11-27
US60/333,145 2001-11-27

Publications (1)

Publication Number Publication Date
WO2003037343A1 true WO2003037343A1 (fr) 2003-05-08

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PCT/EP2002/011201 WO2003037343A1 (fr) 2001-10-30 2002-10-07 Composition a base d'acide folique et de carnitine, favorisant la fertilite masculine

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3269389A1 (fr) * 2016-07-11 2018-01-17 Laboratoire des Granions Composition comprenant de la l-carnitine pour le traitement de l infertilite masculine

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0539336A1 (fr) * 1991-10-21 1993-04-28 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Utilisation de la L-carnitine ou d'acyl L-carnitines pour le traitement des oligoasthenospermies idiopathiques
WO1998033494A1 (fr) * 1997-02-04 1998-08-06 Kosbab John V Compositions et procedes destines a la prevention et au traitement de maladies degeneratives vasculaires
US5904924A (en) * 1997-11-04 1999-05-18 Oncologics, Inc. Green nutritional powder composition
WO2000053176A1 (fr) * 1999-03-05 2000-09-14 Uni-Ci S.R.L. Compositions pharmaceutiques, dietetiques et cosmetiques a base d'acide alpha-lipoique et de cysteine
US6235784B1 (en) * 1997-12-01 2001-05-22 Sigma-Tau Healthscience S.P.A. Medicament and therapeutical method for treating idiopathic asthenozoospermia
US20020122834A1 (en) * 2000-12-22 2002-09-05 Trant Aileen Sontag Method and composition for improving fertility health in female and male animals and humans

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0539336A1 (fr) * 1991-10-21 1993-04-28 Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Utilisation de la L-carnitine ou d'acyl L-carnitines pour le traitement des oligoasthenospermies idiopathiques
WO1998033494A1 (fr) * 1997-02-04 1998-08-06 Kosbab John V Compositions et procedes destines a la prevention et au traitement de maladies degeneratives vasculaires
US5904924A (en) * 1997-11-04 1999-05-18 Oncologics, Inc. Green nutritional powder composition
US6235784B1 (en) * 1997-12-01 2001-05-22 Sigma-Tau Healthscience S.P.A. Medicament and therapeutical method for treating idiopathic asthenozoospermia
WO2000053176A1 (fr) * 1999-03-05 2000-09-14 Uni-Ci S.R.L. Compositions pharmaceutiques, dietetiques et cosmetiques a base d'acide alpha-lipoique et de cysteine
US20020122834A1 (en) * 2000-12-22 2002-09-05 Trant Aileen Sontag Method and composition for improving fertility health in female and male animals and humans

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BENTIVOGLIO GIORGIO ET AL: "Folinic acid in the treatment of human male infertility.", FERTILITY AND STERILITY, vol. 60, no. 4, 1993, pages 698 - 701, XP009005286, ISSN: 0015-0282 *
WALLOCK LYNN M ET AL: "Low seminal plasma folate concentrations are associated with low sperm density and count in male smokers and nonsmokers.", FERTILITY AND STERILITY, vol. 75, no. 2, February 2001 (2001-02-01), pages 252 - 259, XP002230097, ISSN: 0015-0282 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3269389A1 (fr) * 2016-07-11 2018-01-17 Laboratoire des Granions Composition comprenant de la l-carnitine pour le traitement de l infertilite masculine

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